With Greg Berlanti, Guggenheim is the co-creator of the ABC show Eli Stone. He later became executive producer of ABC's No Ordinary Family. Guggenheim, together with Berlanti and Andrew Kreisberg, adapted the Green Arrow comics into the television series Arrow, where Guggenheim serves as co-showrunner.

In 2006, Guggenheim took over the writing of The Flash.[2] Guggenheim's run concluded with the death of the fourth Flash, Bart Allen.

In 2007, Guggenheim became one of the rotating team of writers on The Amazing Spider-Man. His first story appeared in Amazing Spider-Man #549. He also launched a creator-owned comic, Resurrection, for Oni Press.